Signaling and Targeting of CRTC1-MAML2 Fusion Oncoprotein in Salivary Gland

唾液腺中 CRTC1-MAML2 融合癌蛋白的信号传导和靶向

• 批准号: 10208855
• 负责人: Lizi Wu
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-08 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208855
• 关键词: Antisense Oligonucleotides; Automobile Driving; Biology; CREB1 gene; Cell Survival; Cells; Chimeric Proteins; Cyclic AMP; Data; Development; Diagnostic; Disease; Dominant-Negative Mutation; Funding; Fusion Oncogene Proteins; Genes; Genetic Transcription; Genetically Engineered Mouse; Growth; Human; Impairment; In Vitro; Investigation; Lead; MLL/ELL; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of salivary gland; Metastatic/Recurrent; Modeling; Molecular; Mucoepidermoid Carcinoma; Oncogenes; Oncogenic; Outcome; Pathway interactions; Patients; Pattern; Peptides; Permeability; Recurrence; Regulator Genes; Research; Role; Salivary Glands; Signal Transduction; Specificity; Testing; Therapeutic; Tissues; Transgenic Mice; Untranslated RNA; Xenograft procedure; activating transcription factor; cell growth; design; diagnostic biomarker; fusion gene; in vivo; in vivo evaluation; insight; mouse model; novel; novel diagnostics; novel strategies; novel therapeutic intervention; programs; protein protein interaction; prototype; small hairpin RNA; targeted treatment; therapeutic target; transcription factor; tumor; tumorigenesis

Project Summary/Abstract This proposal focuses on the oncogenic CRTC1-MAML2 fusion that underlies the development of mucoepidermoid carcinomas (MEC), the most common type of salivary gland cancers. Patients with advanced, metastatic and recurrent MECs have poor outcomes and no targeted therapy is currently available. A comprehensive understanding of functions and mechanisms of this oncogenic fusion is essential for uncovering effective diagnostic and therapeutic approaches. We demonstrated that the CRTC1-MAML2 fusion is a major driver for MEC initiation and maintenance. Our investigations into the CRTC1-MAML2-induced oncogenic transcriptional program implicated long noncoding RNAs (lncRNAs) in MEC tumorigenesis and maintenance. LncRNAs belong to a novel class of gene regulators with emerging roles in human cancer and have the potential to serve as diagnostic markers due to their tissue and disease specificity. However, the involvement and mechanistic basis of lncRNAs remain poorly defined in MEC. Moreover, our data revealed the interaction of the CRTC1-MAML2 fusion with the transcription factor CREB is critical for inducing the major oncogenic transcriptional program; thus, targeting this interaction interface will have the advantage of blocking multiple critical fusion target genes/pathways. However, the significance of this fusion interaction as a therapeutic target remains to be tested in vivo. Therefore, the objectives of this proposal are to elucidate the lncRNA aspect of the oncogenic transcriptional program in CRTC1-MAML2- driven MEC and the significance of the critical fusion protein interaction governing the oncogenic transcriptional program in MEC. Two aims are proposed to test the overall hypothesis that the CRTC1-MAM2 fusion induces a unique lncRNA program in promoting MEC and that the CRTC1-MAML2/CREB interaction is critical for inducing the major oncogenic transcriptional program in MEC. Consequently, critical lncRNAs and fusion interaction can be targeted for MEC inhibition. Aim 1 will investigate the mechanisms and targeting of lncRNAs in CRTC1- MAML2 fusion-driven tumorigenesis. Aim 2 will Investigate the significance and targeting of the CRTC1-MAML2 fusion/CREB interaction in MEC. The completion of these proposed studies will uncover new mechanistic and functional insights into lncRNAs and the CRTC1-MAML2 oncogenic fusion and reveal new approaches for blocking MEC. We anticipate that these efforts will enhance our understanding of the CRTC1-MAML2 fusion oncogene and MEC biology and lead to the identification of novel diagnostic and therapeutic strategies.

项目总结/摘要 该建议的重点是致癌的CRTC 1-MAML 2融合，其是肿瘤发生的基础。 粘液表皮样癌（MEC）是唾液腺癌中最常见的类型。晚期， 转移性和复发性MEC具有不良的结果，并且目前没有靶向治疗。一 全面了解这种致癌融合的功能和机制对于揭示 有效的诊断和治疗方法。 我们证明了CRTC 1-MAML 2融合是MEC启动和维持的主要驱动因素。 我们对CRTC 1-MAML 2诱导的致癌转录程序的研究表明， 非编码RNA（lncRNA）在MEC肿瘤发生和维持中的作用。lncRNA属于一类新的基因， 在人类癌症中具有新兴作用的调节剂，由于 它们的组织和疾病特异性。然而，lncRNA的参与和机制基础仍然很差， 在MEC中定义。此外，我们的数据揭示了CRTC 1-MAML 2融合与转录的相互作用， CREB因子对于诱导主要致癌转录程序至关重要;因此，靶向这种相互作用 界面将具有阻断多个关键融合靶基因/途径的优点。但 这种融合相互作用作为治疗靶点的重要性仍有待于在体内测试。因此，目标 本研究的目的是阐明CRTC 1-MAML 2-L1中致癌转录程序的lncRNA方面。 驱动的MEC和关键融合蛋白相互作用的意义，控制致癌转录 在MEC的计划。提出了两个目的来检验CRTC 1-MAM 2融合诱导细胞凋亡的总体假设。 独特的lncRNA程序促进MEC，CRTC 1-MAML 2/CREB相互作用是诱导MEC的关键。 MEC中的主要致癌转录程序。因此，关键的lncRNA和融合相互作用可以 用于MEC抑制。目的1研究lncRNA在CRTC 1-C12细胞中的作用机制和靶向性。 MAML 2融合驱动的肿瘤发生。目的2将研究CRTC 1-MAML 2的意义和靶向 融合/CREB相互作用。完成这些拟议的研究将揭示新的机制， lncRNA和CRTC 1-MAML 2致癌融合的功能见解，并揭示了新的方法， 阻止MEC。我们预计，这些努力将提高我们的理解CRTC 1-MAML 2融合 癌基因和MEC生物学，并导致新的诊断和治疗策略的鉴定。